RU2627842C2 - Means for left ventricle diastolic function improvement - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: application of 4-[(2-{(2R)-2-((1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, or a salt thereof, of its clathrate complex with cyclodextrin for preparation of means 1) for treatment of diastolic heart failure and/or symptom alleviation; 2) for heart failure treatment, at which the diastolic function is weakened; 3) for left ventricle diastolic function improvement; 4) for left ventricle expansion improvement; 5) for left ventricle selective diastolic function improvement; 6) for diastolic functional insufficiency treatment or improvement; 7) for diastolic dysfunction treatment or improvement.

EFFECT: agent improves diastolic function of the left ventricle itself, without dependence on diuretic influence or vasodilator effect, controls the pathological state of diastolic functional insufficiency and prevents relapse, can prevent dyspnea and death caused by a pathological condition, the agent can alleviate diastolic functional failure for which an effective therapeutic method has not been established.

10 cl, 3 dwg, 5 tbl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to an agent for improving diastolic function of the left ventricle, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene- 1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin, and their use for treating heart failure and / or alleviating the symptom, in particular, use for the treatment of diastolic heart failure and / or symptom relief.

State of the art

Heart failure is a condition in which the function of the heart pump deteriorates due to various reasons and the blood volume corresponding to the oxygen demand of the peripheral organs cannot be pumped absolutely or relatively, and a condition in which congestion in the lungs or in the venous system is caused a large circle of blood circulation or in both systems, and the disorder is caused in everyday life. The quality of life of patients with heart failure is markedly deteriorating due to symptoms such as shortness of breath during physical exertion, shortness of breath, anxiety, decreased urine volume, swelling of the extremities, and enlarged liver.

It has been established that currently there are more than a million patients with heart failure and their number is definitely increasing from year to year due to the recent westernization of nutritional characteristics and aging of society. In addition, there are several million patients with heart failure, both in the US and in Europe, and this number is expected to increase further in the future. In addition to this, heart failure is known to be one of the diseases with a poor prognosis. For example, it is reported that patients with heart failure generally have a 50% chance of surviving another five years, while patients with severe heart failure have a 30% chance of surviving another three years, and heart failure shows a prognosis comparable to that for cancer. Thus, heart failure is characterized as an extremely serious illness due to the large number of patients and poor prognosis.

In the treatment of heart failure, the therapeutic strategy is usually selected depending on whether the pathological condition of heart failure is chronic or acute.

The so-called chronic heart failure, which refers to a chronic pathological change, is heart failure, showing a progressive exacerbation for a long time, and, as you know, its causes are associated, for example, with myocardial disease or with valve disease. As a treatment for chronic heart failure, for example, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a β-blocker, digitalis, a diuretic agent, an aldosterone antagonist or the like are administered.

On the other hand, the so-called acute heart failure, which refers to an acute pathological change, is a condition in which the filling pressure of the ventricle increases, since the compensation of the pump function of the heart quickly drops and perfusion of the main organs occurs, quickly causing symptoms and signs on its basis. As a treatment for acute heart failure, a diuretic or vasodilator is administered for intravenous administration in order to eliminate the symptoms of stagnation and shortness of breath as quickly as possible, and when perfusion failure is observed, in particular, a cardiotonic agent such as dopamine or dobutamine is used.

As a pathological condition of heart failure, so far only systolic heart failure, which develops systolic functional failure of the left ventricle, has attracted attention. Recently, however, heart failure has also been considered a problem in which the left ventricular ejection fraction (LVEF, an indicator of systolic effort for the left ventricle) is normal or only slightly worsens, namely, the so-called diastolic heart failure.

Diastolic heart failure is known to be common among women and the elderly, in particular among patients with hypertension or diabetes. The anatomical characteristics of the heart in patients with diastolic heart failure are concentric hypertrophy, and the wall of the ventricle thickens and myocardial fibrillation progresses, although there is no difference in heart size compared with healthy individuals. As a result, the ventricle of the heart cannot expand sufficiently during diastole, and it contracts even before it is filled with blood, and thus, a sufficient volume of blood cannot be pumped.

Patients with diastolic heart failure account for approximately half of all patients with heart failure. Although their predictions are comparable to patients with systolic heart failure, most of the therapeutic agents currently used for patients with heart failure are those that are clinically investigated for patients with systolic heart failure with low LVEF. There are no drugs that have the effect of alleviating diastolic functional failure and which have been shown to improve the prognosis for patients with diastolic heart failure.

For the acute exacerbation phase in patients with diastolic heart failure, a diuretic or venodilator vasodilator is used, as is the case for patients with systolic heart failure. However, when such a drug is administered to a patient with diastolic heart failure, there are problems that the volumetric blood flow rate of the heart and blood pressure tend to decrease or the patient is re-hospitalized due to a higher relapse rate compared to a patient with systolic heart failure.

In addition, it is said that most patients diagnosed with systolic heart failure actually suffer from diastolic functional disorder of the left ventricle.

Among the existing drugs used to treat the acute phase, there is no drug that selectively alleviates diastolic functional disorder of the left ventricle, and there are patients with symptoms of pulmonary stasis or shortness of breath who do not relieve or who require a long time to relieve. Thus, a new therapeutic agent is desired.

As described above, in this regard, there is no effective therapeutic method against diastolic heart failure or diastolic functional disorder of the left ventricle, and, therefore, the development of new therapeutic agents is urgently needed.

On the other hand, 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1 -pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its prodrug, or its clathrate complex with cyclodextrin, is a selective EP4 agonist, which is a subtype of the prostaglandin E2 receptor, and is reported to be effective in immune diseases ( autoimmune diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Sjogren's syndrome, chronic rheumatoid arthritis and systemic lupus erythematosus, o retardation after organ transplantation, etc.), with asthma, neuronal death, arthritis, pulmonary failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis (acute nephritis and chronic nephritis), renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki syndrome, with burning sensation, systemic granuloma toze, ulcerative colitis, Crohn’s disease, dialysis hypertoxinemia, multiple organ failure, shock, stomach ulcer, peptic ulcer, such as duodenal ulcer, stomatitis, alopecia, alopecia, bone loss, sleep disturbance, thrombosis, with symptoms of lower urine pathways, hyperkalemia, neurodegenerative disease, and the like (see patent documents 1, 2, 3 and 4).

In addition, it is described that a selective EP4 agonist exhibits renal vasodilator activity, and is thus effective in renal failure or renal dysfunction or in a condition such as congestive heart failure caused by renal failure or renal dysfunction (see Patent Document 5) .

On the other hand, it is also known that a compound having an antagonistic effect on EP4 has a therapeutic effect on heart failure (see patent document 6).

As described above, there is conflicting evidence as to whether EP4 works promoter or inhibitory in the pathological condition of heart failure, and thus the situation is that there is no definite scientific evidence. Among other things, there is no description or evidence that 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its prodrug or its clathrate complex with cyclodextrin, which is an EP4 agonist, has the effect of improving left ventricular diastolic function and acts therapeutically on patients with heart failure, in particular in patients with diastolic heart failure.

Prior Art Documents

Patent documents

Patent Document 1: WO2003 / 009872

Patent Document 2: WO2006 / 016689

Patent Document 3: WO2006 / 016695

Patent Document 4: JP-A-2006-321737

Patent Document 5: JP-A-2001-233792

Patent Document 6: WO2002 / 016311

SUMMARY OF THE INVENTION

Problems to be Solved by the Invention

Diastolic heart failure is a disease caused by diastolic functional heart disorder, in particular, the left ventricle. Since there is currently no drug showing the effects of improving diastolic function of the left ventricle per se, there is no effective drug therapy that can also preferably treat diastolic heart failure.

For patients with diastolic heart failure in the acute exacerbation phase, a diuretic or vasodilator is sometimes prescribed to relieve symptoms of stagnation in the lungs and shortness of breath. However, the diastolic functional disorder of the left ventricle, which is the cause of its pathology, is not treated, and relapses cannot be prevented.

Namely, the aim of the present invention is to provide a medicament that improves the diastolic function of the left ventricle itself, without dependence on diuretic effect or vasodilator effect; controls the pathological state of diastolic heart failure or diastolic functional disorder of the left ventricle and prevents relapse, and can prevent shortness of breath and death due to this pathological condition.

Problem Solving Tools

EP4 agonists are generally predicted to alleviate stagnation in patients with heart failure, as EP4 agonists have a vasodilating effect and an effect of alleviating renal dysfunction. However, these effects are the same as the effects of existing vasodilators, and thus diastolic heart failure or diastolic functional disorder of the left ventricle is not alleviated. Accordingly, when an EP4 agonist is administered to a patient with diastolic heart failure, it is possible that the agonist only causes problems similar to problems for a diuretic or vasodilator, for example, a decrease in the volumetric flow rate of the heart, lowering blood pressure, or frequent relapses.

As a result of extensive research, the authors of the present invention found that among the compounds known as agonists of EP4, 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy- 1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid (sometimes referred to abbreviated below as compound A) improves left ventricular diastolic function through direct exposure to the heart and can effectively treat, in particular diastolic functional failure / diastolic functional disorder among types of heart failure, and, thus, the authors completed the present invention.

Namely, the present invention is as follows.

1. A tool for improving the diastolic function of the left ventricle, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene-1- yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

2. The agent of paragraph 1 above, which is an agent for treating heart failure and / or symptom relief.

3. The tool according to the above paragraph 2, where the heart failure is acute heart failure or chronic heart failure.

4. The tool according to the above item 2 or 3, where the heart failure is diastolic heart failure.

5. The remedy according to paragraph 2 above, where the symptom is stagnation, shortness of breath, shortness of breath, restlessness, decreased urine volume, swelling of the extremities and / or enlarged liver.

6. The tool according to the above items 1-5, which, in addition, has the effect of improving the systolic function of the left ventricle.

7. The agent of paragraph 6 above, which is an agent for treating systolic heart failure and / or alleviating symptoms.

8. The remedy according to paragraph 7 above, where the symptom is stagnation, shortness of breath, shortness of breath, restlessness, decreased urine volume, swelling of the extremities and / or enlarged liver.

9. A tool for improving survival in heart failure, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene-1- yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

10. Means for improving the expansion of the left ventricle, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl ] -5-oxo-1-pyrrolidinyl} ethyl) -thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

11. An agent for preventing myocardial fibrillation that contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

12. The drug for the treatment of heart failure, which is obtained by combining 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene-1 -yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin with one or more compounds selected from an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, β -blocker, digitalis drug, diuretic, natriuretic peptide, vasodilator, f inhibitor sfodiesterazy III and / or aldosterone antagonist.

13. An agent for treating diastolic heart failure and / or symptom relief, which includes a medicament having the effect of improving systolic function of the left ventricle and the effect of improving diastolic function of the left ventricle, where the agent improves diastolic function of the left ventricle more selectively compared to systolic function of the left ventricle .

14. The tool according to the above item 13, where the tool is 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene-1 -yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

15. A tool for the selective improvement of diastolic function of the left ventricle, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene-1 -yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin as the active ingredient, and which selectively improves the diastolic function of the left ventricle compared with systolic function of the left ventricle .

16. The agent of paragraph 15 above, which is an agent for treating diastolic heart failure and / or alleviating symptoms.

17. A treatment for heart failure, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin as an active ingredient, and which alters the positive peak dP / dt and the negative peak dP / dt of a mammal having a pathological heart failure state, where the ratio of the change in the negative peak dP / dt calculated from the values before and after the introduction of the drug is greater than the ratio of the change positive peak dP / dt.

18. The agent of paragraph 17 above, which is an agent for treating diastolic heart failure and / or symptom relief.

19. An agent for preventing the occurrence of heart failure associated with hypertension, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene -1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

20. An agent for treating diastolic heart failure and / or symptom relief that contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1- buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

21. An agent for the treatment of heart failure, in which diastolic function is weakened, which contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1- buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin.

22. A tool for improving the functional state of the heart, which contains 4 - [(2 - {(2R) -2 - ((1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl ] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its complex with cyclodextrin.

23. A method for improving the diastolic function of the left ventricle, where 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin is administered to the mammal.

24. A method for treating heart failure and / or symptom relief, where 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-butene-1 -yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin is administered to the mammal.

25. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for improving diastolic function of the left ventricle.

26. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for treating heart failure and / or relieving symptoms.

27. Compound 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to improve diastolic function of the left ventricle.

28. Compound 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin for the treatment of heart failure and / or symptom relief.

29. A remedy for reducing the dose of an existing treatment for heart failure that contains 4 - [(2 - {(2R) -2 - [(1E, 3S) - (4-fluorophenyl) -3-hydroxy-1-butene-1 -yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its complex with cyclodextrin.

30. An agent for reducing the side effects of an existing agent for treating heart failure that contains 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1- buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its complex with cyclodextrin.

Effects of the invention

Since 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid (compound A), its salt, its solvate or its prodrug, or its clathrate complex with cyclodextrin (sometimes abbreviated hereinafter as “the compound used for the agent of the present invention”) has the effect of alleviating diastolic functional disorder of the left ventricle through direct exposure to the heart, in addition to the vasodilating effect, it is effective, in particular, with di stolicheskoy heart failure, including acute and chronic congestive heart failure, and may alleviate pulmonary congestion, wheezing, shortness of breath, restlessness, a decrease of urine volume, limb swelling, enlarged liver and / or the like is more effective than existing vasodilators. In addition, diastolic function of the left ventricle, as a rule, is weakened also in systolic heart failure and existing diuretic agents / vasodilators cannot alleviate diastolic functional disorder of the left ventricle. Accordingly, the compound used for the agent of the present invention is expected to have better efficacy also in systolic heart failure compared with existing diuretic agents / vasodilators.

Brief Description of the Drawings

[Figure 1] Figure 1 shows a balance of the intensity of left ventricular relaxation effects and left ventricular contraction effects for compound A and milrinone, which is an existing treatment for heart failure in a model of acute heart failure.

[Figure 2] Figure 2 shows the effect of compound A and milrinone on survival in a model of chronic heart failure.

[Figure 3] Figure 3 shows the effect of compound A and milrinone on the left ventricular wall diastolic insufficiency index (DWS) in a model of chronic heart failure.

The method of carrying out the invention

The compound used for the agent of the present invention improves the diastolic function of the left ventricle and can alleviate the condition in which the diastolic function of the left ventricle is weakened, namely, diastolic functional failure of the left ventricle (which is sometimes referred to simply as diastolic functional failure).

In the present description, heart failure includes heart failure in the acute phase or in the chronic phase, namely, acute heart failure or chronic heart failure. The definition of acute heart failure sometimes includes chronic heart failure in the acute exacerbation phase. In addition, heart failure is sometimes called congestive heart failure.

Regarding heart failure, functional heart disorders and the pathological conditions caused by these disorders are shown in table 1 below. Diastolic heart failure (heart failure with diastole) is a heart failure in which only the diastolic function of the left ventricle is weakened, but the systolic function is normal or only slightly worsened. On the other hand, with systolic heart failure (heart failure with systole), both systolic function and diastolic function of the left ventricle are weakened. Diastolic heart failure and systolic heart failure are sometimes called diastolic heart failure and systolic heart failure, respectively. In addition, a condition in which diastolic function of the left ventricle is weakened is called diastolic functional disorder of the left ventricle, diastolic functional failure of the left ventricle, diastolic disorder of the left ventricle, or diastolic insufficiency of the left ventricle; and a condition in which systolic function is weakened is also called systolic functional disorder of the left ventricle, systolic functional failure of the left ventricle, systolic disorder of the left ventricle, or systolic failure of the left ventricle.

Table 1 Function Diastolic function Systolic function Pathological condition Diastolic heart failure (diastolic heart failure) weakened normal Systolic heart failure (systolic failure) weakened weakened

Since the compound used for the agent of the present invention improves left ventricular diastolic function and further reduces afterload and preload of the heart, causing arteriovenous relaxation, the compound is effective in systolic heart failure, in which both systolic function and diastolic function are weakened, as well as diastolic heart failure, in which diastolic function is weakened.

The compound used for the agent of the present invention is 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] - 5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid (which is sometimes referred to as "compound A" in the present description), namely, the compound represented by the following formula,

(in the formula

represents a relationship on the opposite side of the plane of this page (namely, (α-position)),

represents a bond on our side of the plane of this page (namely, (β-position)), its salt, its solvate, its prodrug or its clathrate complex with cyclodextrin is a compound described in WO2003 / 009872.

The salt of compound A includes all pharmacologically acceptable salts. Pharmacologically acceptable salts are preferably low toxic, water soluble salts. Suitable salts include, for example, alkali metal salts (such as potassium, sodium and lithium), alkaline earth metal salts (such as calcium and magnesium), ammonium salts (such as tetramethylammonium salt and tetrabutylammonium salt), salts of organic amines (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine and N-methyl-D-glucamine), acid addition salts (such as salts of inorganic acids (e.g. hydroorganic salts chloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate), and salts of organic acids (e.g. acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, gluconionate, isethionate gluconate)).

Suitable solvates of compound A include, for example, solvates such as hydrates and solvates of alcohols (e.g. ethanol). It is preferred that the solvate be low toxic and water soluble. In addition, the solvate of compound A also includes solvates of salts of compound A (such as alkali (alkaline earth) metal salts, ammonium salts, organic amine salts and acid addition salts).

As a prodrug of compound A, for example, compounds are considered in which the carboxyl group of compound A or its salt is esterified or amidated (for example, compounds in which the carboxyl group of compound A is methyl esterified, ethyl esterified, propyl esterified, butyl- esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1 - {(ethoxycarbonyl) oxy} ethyl esterified, ft alidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, 1 - {[(cyclohexyloxy) carbonyl] oxy} ethyl esterified or methyl amidated).

Compound A, its salt, its solvate or its prodrug can be converted to the corresponding clathrate complex with cyclodextrin using the method described in the description of JP-B-50-3362, JP-B-52-31404 or JP-B-61-52146 using α-, β- or γ-cyclodextrin or a mixture thereof, as necessary.

In this regard, some kind of any compound A itself can be used, its salt, its solvate, its prodrugs and its clathrate complex with cyclodextrin, or two or more kinds thereof can be used as a mixture.

[Method for preparing the compound used for the agent of the present invention]

4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1-pyrrolidinyl} ethyl ) thio] butanoic acid, its salt, its solvate, its prodrug or its clathrate complex with cyclodextrin can be obtained using known methods described above, for example, the methods described in WO2003 / 009872, by combining the methods described in JP- B-50-3362, JP-B-52-31404 or JP-B-61-52146, as needed.

[Toxicity]

The toxicity of the compound used for the agent of the present invention is very low, and the compound is safe enough to be used as a medicine. For example, it was not found that Compound A is toxic even when the dose reaches 30 times the dose at which a vasodilating effect is observed with at least one administration, with repeated oral administration to the dog for four weeks.

[Application in pharmaceutical preparations]

The compound used for the agent of the present invention has the effect of improving diastolic function of the left ventricle, and is thus effective in heart failure (acute heart failure or chronic heart failure). The compound is effective, in particular, in heart failure, in which the ejection fraction of the left ventricle is normal or only slightly worsened, namely, with diastolic heart failure among types of heart failure. Diastolic heart failure is sometimes called diastolic heart failure. In addition, since the compound used for the agent of the present invention improves the diastolic function and systolic function of the left ventricle and reduces the afterload and preload of the heart, causing arteriovenous relaxation, the compound is effective in systolic heart failure, in which both systolic function and diastolic function are weakened. function, as well as for diastolic heart failure, in which diastolic function is weakened.

By administering the compound used for the agent of the present invention to a patient with diastolic functional impairment or systolic functional impairment, the compound may alleviate pulmonary congestion, shortness of breath, shortness of breath, anxiety, decreased urine volume, swelling of the extremities, enlarged liver and / or anything similar associated with pathological conditions.

In addition, as will be explained in the following examples, the compound used for the agent of the present invention is also useful as an agent for improving survival in heart failure, an agent for improving left ventricular dilatation, and an agent for preventing myocardial fibrillation. In addition, the compound used for the agent of the present invention is also useful as an agent for improving the quality of life and an agent for improving the functional state of the heart.

In this document, improved heart failure survival means that survival is improved when the compound used for the agent of the present invention is administered to a mammal (human, dog, rat, or the like) that has already developed heart failure compared to the case without introduction. For example, it is said that patients with heart failure generally have a 50% chance of surviving another five years, and this five-year survival rate can be improved to about 60% or more, preferably to about 70% or more, and even more preferably to about 80% or more when the agent of the present invention is administered. Even when survival does not improve, congestion, shortness of breath, shortness of breath, anxiety, decreased urine volume, swelling of the extremities, enlarged liver and / or the like, are improved, and thus, the quality of life is also improved.

As used herein, preventing myocardial fibrillation means that the development of myocardial fibrillation is prevented when the compound used for the agent of the present invention is administered repeatedly to a mammal (human, dog, rat, or the like) that has already developed heart failure, compared to case without introduction. Prevention of myocardial fibrillation leads to the prevention of a worsening of left ventricular expansion (namely, passive diastolic disorder of the left ventricle), and thus diastolic functional disorder of the left ventricle is facilitated.

In addition, as described above, in a patient with diastolic heart failure, the ventricle cannot expand sufficiently during diastole, and sufficient blood cannot be pumped due to thickening of the ventricular wall and myocardial fibrillation. Since the compound used for the agent of the present invention prevents myocardial fibrillation and prevents deterioration of the expansion of the left ventricle, the compound can be used as an agent to improve the functional state of the heart. It can be easily measured and decided whether the compound used for the agent of the present invention improves the cardiac volume flow rate using an invasive, non-invasive or minimally invasive device for monitoring the cardiac volume flow rate.

In order to use the compound used for the agent of the present invention for the above purpose, the compound used for the agent of the present invention can typically be administered systemically or topically in the form of oral or parenteral administration after appropriate preparation of the compound. As parenteral administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, and the like are considered. The route of administration of the compound used for the agent of the present invention can be any method insofar as it is a method that makes it possible to intravitally administer an effective amount thereof, and, for example, oral administration or administration by injection, or administration as a patch, is preliminary. .

Although the dose depends on age, body weight, symptom, therapeutic effect, route of administration, period of administration, and the like, as a rule, the administration is oral and is carried out once or several times a day, where the amount each time is from 0.1 ng to 1 mg for an adult, parenteral, and once a few times a day, where the amount each time is from 0.1 ng to 1 mg for an adult, or intravenously and continuously, for 1 hour to 24 hours a day. For example, when the compound used for the agent of the present invention is administered orally, the compound is preliminarily administered once to five times a day, the amount each time being from 100 ng to 10 μg for an adult.

It is not necessary to say that a dose lower than the above dose may be sufficient, or it may be necessary to administer a dose in excess of the specified range, since the dose varies under different conditions, as described above.

In addition, the compound used for the agent of the present invention can be administered to a patient with heart failure after combining the compound with an existing agent for treating heart failure, such as an angiotensin converting enzyme inhibitor (such as enalapril, lisinopril, ramipril, captopril, benazepril, fosinopril, moexipril, perindopril, hinapril or trandolapril), an angiotensin II receptor antagonist (such as valzartan, candesartan, losartan, eprosartan, irbesartan or telmisartan), si mpatomimetic agent (such as dopamine or dobutamine), β-blocker (such as carvedilol, bisoprolol or metoprolol), digitalis preparation (such as digoxin or digitoxin), diuretic agent (such as furosemide, bumetanide, triamterene, trichloromethiazide, azosemide, ethacrylic acid or amiloride), a natriuretic peptide (such as carperitide or neziritide), a vasodilator (such as nitroglycerin, isosorbide dinitrate, nicardipine, nicorandil or colforsin daropath), a phosphodiesterase III inhibitor (such as milrinone, aminophylline, pimobendan or olprinone) or an aldosterone antagonist (such as spironolactone or eplerenone). The compound used for the agent of the present invention and the aforementioned agent for treating heart failure can be administered simultaneously with the preparation of a combined pharmaceutical preparation containing both substances. Alternatively, both the compound and the agent can be prepared and administered individually or simultaneously.

By combining the compound used for the agent of the present invention with an existing agent for treating heart failure, the dose of an existing agent for treating heart failure can be reduced, or the occurrence of an adverse event, which is usually called side effect, can be prevented. Namely, the compound used for the agent of the present invention is also useful as an agent for reducing the doses of the agent for treating heart failure mentioned above, or as an agent for alleviating side effects.

As means for preparing a pharmaceutical preparation, when a compound used for the agent of the present invention is administered, a solid agent for internal use and a liquid agent for internal use, for oral administration, and a drug for injection, for parenteral administration, agent for external use, suppository are considered , inhalant or something like that. The compound used for the agent of the present invention can be formulated as a pharmaceutical preparation by a known method, for example, the method described in WO2003 / 009872.

A solid oral preparation for oral administration includes a tablet, pill, capsule, powder, granules and the like. The capsule includes a hard capsule and a soft capsule. In addition, the tablet includes a sublingual tablet, an intraoral patch, an intraoral quick-loosening tablet, and the like.

In such a solid internal agent, the compound used for the agent of the present invention is used as is or after mixing with an excipient (such as lactose, mannitol, glucose, microcrystalline cellulose or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or metasilicoaluminate magnesium), a disintegrant (such as calcium fibrinoglycolate), a lubricant (such as magnesium stearate), a stabilizer, a solubilizing agent (such as glutamic acid or aspartic acid), and the like, followed by preparation in the form of a pharmaceutical preparation using a conventional method. Furthermore, if necessary, the solid agent may be coated with a coating agent (such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl methylcellulose phthalate) or may be coated with two or more layers. In addition to this, a capsule from an absorbable substance such as gelatin is also included.

A sublingual tablet is prepared and prepared in accordance with a known method. For example, the compound used for the agent of the present invention is mixed with an excipient (such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silicon dioxide or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), such as a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium or calcium fibrinoglycolate), a lubricant (such as magnesium stearate), a swelling agent ( such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carbopol, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum or guar gum), an auxiliary substance that causes swelling (such as glucose, fructose, mannitol, xylitol, erythritol, maltose, glycate, phosphate, glutamic acid or arginine), a stabilizer, a solubilizing agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), a flavor (such as orange, strawberry, mint , Lemon, or vanilla) and the like; prepared in the form of a pharmaceutical preparation using the usual method and use. Furthermore, if necessary, the sublingual tablet may be coated with a coating agent (such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate), or it may be coated with two or more layers. In addition to this, an additive such as a preservative, an antioxidant, a coloring agent and a sweetener, which are typically used, can be added if necessary.

A tablet of an intraoral patch is prepared and prepared in accordance with a known method. For example, the compound used for the agent of the present invention is mixed with an excipient (such as lactose, mannitol, glucose, microcrystalline cellulose, colloidal silicon dioxide or starch), a binder (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), such as a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium or calcium fibrinoglycolate), a lubricant (such as magnesium stearate), an adhesive agent (such as droxypropyl cellulose, hydroxypropyl methyl cellulose, carbopol, carboxymethyl cellulose, polyvinyl alcohol, xanthan gum or guar gum), an adhesive adjuvant (such as glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, arginate, phosphate, gilgitin, phosphate, glycate ), a stabilizer, a solubilizing agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), a flavor (such as orange, strawberry, mint, lemon or vanilla), and th like; prepared in the form of a pharmaceutical preparation using the usual method and use. In addition, if necessary, the tablet of the intraoral patch may be coated with a coating agent (such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate), or it may be coated with two or more layers. In addition to this, an additive such as a preservative, an antioxidant, a coloring agent and a sweetener, which are typically used, can be added if necessary.

An intraoral fast loosening tablet is prepared and prepared in accordance with a known method. For example, the compound used for the agent of the present invention is used as is or as an active ingredient in which a certain volume of powder or particle size of granular powder is coated using an appropriate coating agent (such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or an acrylic acid copolymer and methacrylate) and a plasticizer (such as polyethylene glycol or triethyl citrate), followed by mixing with a filler (such as varnish oza, mannitol, glucose, microcrystalline cellulose, colloidal silicon dioxide or starch), a binder (such as hydroxypropyl cellulose, polyvinyl pyrrolidone or magnesium metasilicate caluminate), a disintegrant (such as starch, L-hydroxypropyl cellulose, carboxymethylcellulose, carboxymethylmethylcellulose) (such as magnesium stearate), a dispersing adjuvant (such as glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine , glutamic acid or arginine), a stabilizer, a solubilizing agent (such as polyethylene glycol, propylene glycol, glutamic acid or aspartic acid), a flavoring agent (such as orange, strawberry, mint, lemon or vanilla), and the like, with a pharmaceutical preparation using the usual method. In addition, if necessary, the intraoral rapidly loosening tablet may be coated with a coating agent (such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl methyl cellulose phthalate), or it may be coated with two or more layers. In addition to this, an additive such as a preservative, an antioxidant, a coloring agent and a sweetener, which are typically used, can be added if necessary.

A liquid agent for internal use, for oral administration, includes pharmaceutically acceptable water, suspension, emulsion, syrup, elixir, and the like. In such a liquid agent, the compound used for the agent of the present invention is dissolved, suspended or emulsified in a commonly used diluent (in purified water, ethanol, a liquid mixture or the like). In addition, the liquid agent may further comprise a wetting agent, suspending agent, emulsifying agent, sweetener, flavoring agent, fragrance, preservative, buffer, and the like.

An injectable preparation for parenteral administration includes a solid injectable preparation which is used by dissolving or suspending in a solution, suspension, emulsion or in a solvent prepared directly for use. An injection preparation is used by dissolving, suspending or emulsifying the compound used for the agent of the present invention in a solvent. The solvent used is, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, an alcohol such as ethanol, and a combination thereof. In addition, this injection preparation may include a stabilizer, a solubilizing agent (such as glutamic acid, aspartic acid or polysorbate 80 (registered trade name)), a suspending agent, an emulsifying agent, a sedative, a buffer, a preservative, and the like. They are sterilized in the final method or obtained and prepared by aseptic manipulation. In addition, an aseptic solid can be obtained, for example, a product obtained by freeze-drying, and then it can be used by dissolving during sterilization or in sterilized distilled water for injection or in other solvents before use.

The patch is prepared using a known or commonly used preparation. For example, a patch is prepared by melting the compound used for the agent of the present invention, in the base and applying it, we level it on the substrate. The base for the patch is selected from known or commonly used bases. For example, a species selected from polymer bases (such as a styrene-isoprene-styrene block copolymer, polyisobutylene rubber, an acrylic ester resin, an acrylic copolymer resin and silicone rubber), from fat and oil, higher aliphatic acids, means to accelerate penetration through the skin (such as oleic acid, isopropyl myristate, D-menthol or crotamiton), tackifiers (such as rosin derivatives and alicyclic saturated hydrocarbon resin), means to prevent irritation tions (such as glycerin and Crotamiton), used by themselves or mixed and used two or more kinds thereof. In addition, a preservative, an antioxidant, a flavoring agent, and the like may be included. As a patch, for example, bandages (such as a matrix-type patch (such as an adhesive single layer) and a reservoir-type patch), compresses, and the like are considered. The matrix type patch further includes a matrix type patch with drug distribution, a matrix type patch with drug dissolution, and the like. The substance for dressings is also called a tape tool.

Examples

Although the present invention is explained in detail in the Examples below, the present invention is not limited to these examples.

(1) Assessment of hemodynamics in a model of acute heart failure

<Preparation of animal models>

A model of acute heart failure is obtained using the following method. Beagle male dogs (weight over 10 kg) are anesthetized with sodium pentobarbital (30 mg / kg, intravenous), and then a tracheal catheter is inserted into the trachea and connected to an artificial respiration apparatus. The respiratory rate of the artificial respiration apparatus is set at 15 beats per minute; the ventilation value is set at 20 ml / kg per stroke and respiration is controlled using a gas mixture (air: O ₂ = 3: 0.2, as an indicator). The animal is fixed in a lateral position and the hair is sheared from the left side of the chest, from the left and right femoral regions and from the cervical region. Sodium pentobarbital (5 mg / kg / h) is continuously administered intravenously from the right cerebral vein and anesthesia is maintained. The chest is opened on the left fourth rib and the beginning of the ascending aorta is hushed. Ringer's lactate solution is continuously administered intravenously from a catheter inserted into the left femoral vein (5 ml / min). In addition, to prevent the occurrence of arrhythmias, propanolol hydrochloride (0.3 ml / min) is continuously administered along with volume overload of the heart (mixed with Ringer's lactate solution) until the end of the experiment. The left anterior descending coronary artery (LAD) is ligated 30 minutes after administration of Ringer's lactate solution. After hemodynamics becomes stable, methoxamine hydrochloride is continuously injected from the left femoral vein. To increase systemic vascular resistance and, thus, reduce the volumetric flow rate of the heart, methoxamine hydrochloride is maintained at a volume of 5 to 10 μg / kg / min, so that the volumetric flow rate of the heart decreases by 20% or more compared to the volumetric flow rate of the heart before volume overload of the heart, and methoxamine hydrochloride is continuously administered until the experiment is completed.

<Introduction of the test compounds>

From the point in time at which the volumetric blood flow rate of the heart decreases by 20% or more after the start of continuous administration of methoxamine hydrochloride compared to the volumetric blood flow rate of the heart before the administration of the lactate solution of Ringer and others, the hemodynamics become stable, physiological saline solution (0.3 ml / min) from the right femoral vein for 30 minutes (before the injection phase). Then compound A, methyl ester (11α, 13E, 15α) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-eno acids (EP4 agonist described in Example 1 of WO2000 / 003980, abbreviated Compound B, below) and carperitide (atrial natriuretic peptide), nitroglycerin (a vasodilator), nicorandil (a vasodilator), and milrinone (a phosphodiesterase III inhibitor; a compound having a cardiac exposure and vasodilator effects), which are pre-existing treatments for cardiac sufficiency, administered within 30 minutes, each, with a gradual increase in dose from the right femoral vein at the doses indicated in the following table. Groups for administration (four examples each) and doses are shown below.

table 2 Group for introduction Dose
(administration at two increasing doses) Carrier Physiological saline Compound A 3, 10 mcg / kg / min Compound B 3, 10 mcg / kg / min Carperitid 0.3, 1 mcg / kg / min Nitroglycerine 1, 3 mcg / kg / min Nicorandil 10, 30 mcg / kg / min Milrinon 1, 3 mcg / kg / min

Measurement of cardiac hemodynamics is carried out every 10 minutes both in the phase preceding administration and during the continuous administration of each dose.

<Measurement of hemodynamics>

Through a catheter insertion device inserted into the right femoral artery, a visualization catheter with a curl at the end is inserted and placed continuously in the left ventricle, and connected to a disposable blood pressure sensor, and the left ventricular pressure (LVP) is measured using a measurement amplifier. In addition, using hemodynamic analysis software, left ventricular end diastolic pressure (LVEDP: preload indicator), systemic vascular resistance (SVR; afterload indicator), cardiac volume flow rate (CO), positive peak dP / dt (peak + dP / dt: rate of left ventricular systolic function), negative peak dP / dt (peak-dP / dt: rate of left ventricular diastolic function), urine volume and arterial oxygen pressure (PaO _2: ability to measure blood oxygenation in the lungs, and enshenie PaO ₂ indicates the abnormality of the respiratory system, i.e., to respiratory failure) were analyzed by the waveform LVP.

<Results>

The ratios of the change (%) of the negative peak dP / dt 60 minutes after the administration of the test compounds are shown in Table 3 below, and the ratios of the change (%) of the negative peak dP / dt and the ratios of the change (%) of the positive peak dP / dt of compound A and milrinone shown in figure 1.

Table 3 Negative peak change ratio dP / dt (%) Compound A 48 Compound B -3 Carperitid -6 Nitroglycerine -8 Nicorandil -7 Milrinon 23

As shown in table 3, compound A shows a stronger effect of improving diastolic function of the left ventricle compared to carperitide, nitroglycerin, nicorandil and milrinone, which are already existing treatments for heart failure. In addition, compound A increases the volumetric flow rate of the heart by about 60%.

In addition, as shown in FIG. 1, compound A shows a milder effect of improved systolic function (peak change ratio + dP / dt = 16%) compared with the effect of improved diastolic function. On the other hand, with respect to milrinone, which is an existing treatment for heart failure, the effect of improving systolic function (peak change ratio + dP / dt = 38%) is stronger than the effect of improving diastolic function, and the cardiotonic effect is excellent. From the above results, it follows that milrinone is not always suitable for administration to a patient with diastolic heart failure with normal systolic function, since milrinone has a strong cardiotonic effect, while compound A selectively improves left ventricular diastolic function compared to the effects of improved systolic function , and, thus, is also effective for a patient with diastolic heart failure with normal systolic function, and t Also for a patient with systolic heart failure who has weakened both diastolic function and systolic function. In addition, although milrinone shows strong systolic effects for the left ventricle also in a normal dog, Compound A does not show diastolic effects for the left ventricle or systolic effects for the left ventricle in a normal dog. Accordingly, compound A has a marked effect, showing a pathologically specific diastolic effect for the left ventricle and systolic effect for the left ventricle. In addition, compound A also improves urine volume and blood pressure of oxygen (urine volume change ratio = l45.4% and PaO ₂ change ratio = 111.5%).

In addition, as shown in table 4, below, since the ratios of changes in the final diastolic pressures of the left ventricle and systemic vascular resistances for compound A and compound B, known as an EP4 agonist, are almost the same, compound A and compound B show similar vasodilator effects, but Compound B does not show the effects of improved diastolic function or the effects of improved systolic function (peak change ratio + dP / dt = -4%; peak change ratio-dP / dt = -3%).

Table 4 Change ratio (%) Compound A Compound B The final diastolic pressure of the left ventricle -42 -41 Systemic vascular resistance -34 -43 Positive peak dP / dt 16 -four Negative peak dP / dt 48 -3

It can be seen from the above results that the compound used for the agent of the present invention can be a useful agent for the treatment of acute heart failure, since the compound has a strong effect of improving diastolic function of the left ventricle directly on the heart, as well as a mild effect of improving systolic function, which do not already have existing EP4 agonists, such as compound B. In addition, it has been shown that symptoms of decreased urine volume, shortness of breath, and the like, with heart failure can also be alleviated.

(2) Comparison of the effects of compound A and structurally similar compounds in a model of acute heart failure

In an experiment similar to experiment (1) above, the effects of improving left ventricular diastolic function were evaluated for the following EP4 agonists having structures similar to compound A.

Compound C: the compound described in example 2 of JP-A-2001-18121210 (dose: 3 μg / kg / min)

Compound D: the compound described in example 5 WO2003 / 007941 (dose: 1 μg / kg / min)

Doses of compounds C and D are amounts showing vasodilating effects equivalent to those of compound A.

<Results>

As shown in table 5 below, compound C and compound D do not show the effects of improved diastolic function or effects of improved systolic function, at doses showing vasodilating effects, almost equivalent to the effects of compound A.

Table 5 Change ratio (%) Compound C Compound D The final diastolic pressure of the left ventricle -37 -46 Systemic vascular resistance -fourteen -42 Positive peak dP / dt 2 -9 Negative peak dP / dt -one -5

From the above results, it is seen that the direct and strong effect of improving the diastolic function of the left ventricle, which has the compound used for the agent of the present invention, is a significant effect that is not shown by compounds having structures similar to the structure of compound A.

(3) Measurement of cardiac function and survival assessment using Dahl rats

<Cooking animal model>

A model of heart failure in hypertension, which is diastolic heart failure, is prepared by feeding solid food for rats with a high salt load (corresponding to 8% salt) to male DIS / Eis rats (Dahl rats) aged 47 days. Solid food for rats with a normal diet (corresponding to 0.3% salt) is fed to the normal control group (10 examples).

<Introduction of the test compounds>

The test compounds were administered orally multiple times over 90 days twice a day at a dose of 5 ml / kg using a gastric tube to Dahl rats at 13 weeks of age. The dose of compound A is 300 μg / kg and the dose of milrinone is 1000 μg / kg (30 examples each).

<Evaluation of cardiac function>

Cardiac function is measured using an ultrasound imaging device with 2% isoflurane anesthesia using a general animal anesthesia device before administration (age 12 weeks; value for grouping), on the 45th day of administration and on the 91st day of administration. The coat in the chest of the rat is removed and changes in the final diastolic size of the left ventricle, the final systolic size of the left ventricle, the final diastolic thickness of the anterior wall of the left ventricle, the final diastolic thickness of the posterior wall of the left ventricle, the final systolic thickness of the posterior wall of the left ventricle and the posterior epicardial surface of the left the ventricle is measured by placing a linear sensor on the chest area in M-mode. After that, the left ventricular ejection fraction (LVEF) and the left ventricular wall diastolic insufficiency index (DWS) are calculated as an indicator of the diastolic function of the left ventricle.

<Survival Score>

The general condition is observed once or twice a day during the entire period of the experiments and confirms death or survival, and common symptoms are recorded.

<Results>

The results are shown in figures 2 and 3.

In the Dahl rat heart failure model, which is known as the chronic heart failure model, compound A significantly improves DWS. This means that deterioration of the expansion of the left ventricle due to heart failure, that is, myocardial fibrillation, is prevented, and diastolic function of the left ventricle improves. In addition, compound A dramatically increases survival.

On the other hand, milrinone, which is an existing treatment for heart failure, does not improve DWS, and the degree of improvement in survival is small compared to compound A.

From the above results, it can be seen that the compound used for the agent of the present invention has a strong effect of improving diastolic function of the left ventricle and increases survival, and thus may be a useful agent for treating chronic heart failure.

In addition, since the prognosis of heart failure for hypertension is significantly improved, it has been shown that the compound used for the agent of the present invention can be an agent for preventing the occurrence of heart failure associated with hypertension.

<Pharmaceutical Example>

Representative examples of a pharmaceutical preparation used in the present invention are shown below.

Pharmaceutical Example 1: Tablet

According to the usual method, 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo -1-pyrrolidinyl} ethyl) thio] butanoic acid (50 mg), magnesium stearate (10 g), calcium carboxymethyl cellulose (20 g) and microcrystalline cellulose (920 g) are mixed and formed into tablets to give 9000 tablets, each of which contains 5 mcg of active ingredient.

Pharmaceutical Example 2: Injectable

4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] is dissolved in distilled water for injection (30 L)] -5-oxo-1-pyrrolidinyl} ethyl) thio] butanoic acid (50 mg) and mannitol (1500 g), and the solution is filtered for sterilization using a membrane filter. Then, the injection solution, each with a volume of 3 ml, is filled into 5 ml ampoules to obtain an injection preparation (9000 ampoules) containing 5 μg of active ingredient per ampoule.

Industrial application

The compound used for the agent of the present invention has the effect of improving diastolic function and the effect of improving systolic function in the left ventricle. Accordingly, the compound is effective for heart failure (acute heart failure or chronic heart failure), and it is effective, in particular for diastolic functional failure. In addition, the compound is also effective for symptoms such as congestion, shortness of breath, shortness of breath, anxiety, decreased urine volume, swelling of the extremities and / or enlarged liver associated with heart failure.

Therefore, with the present invention, a novel agent for treating heart failure can be proposed that can alleviate diastolic functional failure, for which no effective therapeutic method has been established.

Claims (10)

1. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for the treatment of diastolic heart failure and / or symptom relief. 2. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for the treatment of heart failure, in which diastolic function is weakened. 3. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for improving diastolic function of the left ventricle. 4. The use according to claim 3, which is an application for further improving the systolic function of the left ventricle. 5. The use of claim 4, which is an application for the treatment of systolic heart failure and / or symptom relief. 6. The use according to claim 5, where the symptom is stagnation, shortness of breath, shortness of breath, anxiety, decreased urine volume, swelling of the extremities and / or enlarged liver. 7. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for improving left ventricular dilatation. 8. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for selectively improving diastolic function of the left ventricle, which selectively improves diastolic function of the left ventricle compared to systolic function of the left ventricle. 9. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for the treatment and / or improvement of diastolic functional failure. 10. Application of 4 - [(2 - {(2R) -2 - [(1E, 3S) -4- (4-fluorophenyl) -3-hydroxy-1-buten-1-yl] -5-oxo-1- pyrrolidinyl} ethyl) thio] butanoic acid, its salt, its solvate or its clathrate complex with cyclodextrin to obtain an agent for the treatment and / or improvement of diastolic dysfunction.

Images